AU2009308665B2 - Compositions containing delta-9-THC-amino acid esters and process of preparation - Google Patents
Compositions containing delta-9-THC-amino acid esters and process of preparation Download PDFInfo
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Abstract
Compositions of the formulae (I), (II) and (III); where R1, R2 and R3 are residues of amino acids such as, but not limited to, valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine and 4(4-aminophenyl)butyric acid or combination thereof, and salts thereof. Methods of preparation of these compositions and methods of treating any disease condition responsive to THC comprising administration of at least one these compositions in a pharmaceutically acceptable carrier using a pharmaceutically acceptable formulation.
Description
WO 2010/051541 PCT/US2009/062998 COMPOSITIONS CONTAINING DELTA-9-THC-AMINO ACID ESTERS AND PROCESS OF PREPARATION FIELD OF INVENTION The present invention relates to composition containing delta-9-THC-amino acid esters and their process of preparation. Background of the Invention OH 0 1: Structure of A 9 -Tetrahydrocannabinol (THC). Ag-Tetrahydrocannabinol (THC, 1) is the primary active ingredient of the plant Cannabis sativa (marijuana) and is responsible for the majority of the pharmacological effects. People have utilized the plant (that includes numerous cannabinoids) since ancient times for medicinal purposes as well as for its intoxicating properties. While marijuana is primarily known as an abused drug, we believe that there are important pharmacological properties of the active component THC that could be directed to specific therapeutic effects, given the appropriate delivery mechanism. To date, the most promising clinical applications approved by the Food and Drug Administration (FDA) are for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from anorexia and wasting syndrome [2. THC, however, demonstrates other biological activities which lend themselves to possible additional therapeutic applications. These include glaucoma [, migraine headaches [4. 5] spasticity/epileptic seizures [ 7, anxiety [8] and chemical dependence withdrawal symptoms. Also, more recently, THC is becoming increasingly recognized as an analgesic [', 2, . Due to these promising biological activities, THC has potential for multiple medicinal uses. Challenges in systemic delivery of THC: Parenteral formulations researched include an intramuscular preparation [9] and an intravenous dosage form (neither of which have been approved by FDA). Injectables are inundated with the 1 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 problems of being invasive and requiring professional assistance, and therefore in many cases preclude self medication. In addition, these parenteral routes are inherently subject to abuse. Thus, the search for a non-parenteral delivery system for THC continues. The physicochemical characteristics of THC, like many other lipophilic agents, present major challenges to drug delivery scientists. The logP (log octanol/water partition coefficient) value of THC is around 4.0 indicating that it is a highly lipophilic compound. Consequently, THC's solubility in the gastro-intestinal fluids and partitioning from the intestinal membranes into the systemic circulation would be severely limited. Additionally, THC is rapidly metabolized by the hepatic CYP 450 enzymes to the 11-hydroxy metabolite (11-OH-THC), which is responsible for the undesirable side effects of THC 19. 01. The blood plasma levels desired are in the range of 10 ng/ml-enough to provide a therapeutic effect without the production of a significant "high" (>100 ng/ml) Il 12. Poor gastro-intestinal stability of THC further hinders oral absorption. These factors act in conjunction to minimize systemic availability of THC following peroral administration, the most preferred route of administration, and forms the basis of one of the main issues brought into public debate by medicinal marijuana proponents--the fact that the currently available soft gelatin formulation is expensive and lacks consistency in its therapeutic effects and pharmacokinetic profiles. It is significant to note, however, that the only THC dosage form currently approved by FDA is the oral, soft gelatin capsule (Marinol@). Considering the challenges in intestinal absorption and metabolism, attempts have been made to deliver THC through nasal as well as inhalation routes [1. In a recent phase I pharmacokinetic study [16] performed by GW Pharmaceuticals, UK, Cannabis-based extracts were tested by three different routes of administration via; sublingual, buccal and oropharyngeal. The formulation was administered in the form of sublingual drops as well as a pump action sublingual spray (PASS). In this study, it was reported that buccal administration of the PASS test treatment resulted in a later Tmx but greater Cmax when compared to the sublingual and oropharyngeal routes. However, AUC was reported to be greatest following the oropharyngeal route. The lower bioavailability (measured in terms of AUC) following buccal administration, as compared to the sublingual and oropharyngeal routes, is most likely related to the difficulty of spraying onto the inside of the cheek and subsequent loss of the spray. Although promising, the nasal and oropharyngeal routes are burdened with problems. Potential irritation and the irreversible damage to the ciliary action of the nasal cavity from chronic application of nasal dosage forms, and large intra- and inter-subject variability in mucus secretion in the nasal mucosa that could significantly affect drug absorption from this site. Also, the inhalation route of. administration possesses high abuse characteristics. In addition, spray formulations of THC have 2 SUBSTITUTE SHEET (RULE 26) been shown to have a dosage form-related adverse effect of throat irritation 1 6 3. Other non parenteral routes examined include sublingual 7 3, rectal0 1 720 3 and vaginal . The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Summary of the invention: This invention comprises compositions containing delta-9-THC-amino acid esters, methods of their preparation and their use in the treatment of different disease conditions. This invention also describes methods of preparation of delta-9-THC-amino acid esters. The compositions of this invention have not been previously described. The compounds of this invention represent a class of amino acid esters, one that will improve formulation characteristics and bioavailability of THC. According to a first embodiment of the invention, there is provided a A 9 tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the formula 0 0 R 1 wherein R1 is valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof. According to a second embodiment of the invention, there is provided a A 9 tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the formula wherein R1 and R2 are each valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof. 3 According to a third embodiment of the invention, there is provided a A 9 tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the formula 0 wherein R1, R2 and R3 are each valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof. According to a fourth embodiment of the invention, there is provided the hemisuccinate or hemigluturate derivatives of compositions of the first, second or third embodiments. According to a fifth embodiment of the invention, there is provided a method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with the first embodiment as shown in scheme I H COOH 0 COOH R N 0 H2N R H 2 0, NaHCO 3 O N R DCC, DMAP,DCM T Y
H
2 N R AllyI chloroformate 0 H O C 0 R = amino acid residue A- 2 (Neutral, acidic or basic) OH 1 0 3 0 DCM, phenyl silant THC Tetrakis(triphenylphosphine) palladium Methanol R R NH- C)NH 2 R NH 2 OI ' 0 . IC-' 1)DCC, DMAP,DCM, 2 2) DCM, phenyl silane O Tetrakis(triphenylphosphine) palladium 0 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) comprising the steps of: 1) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid and 4) preparation of the water soluble salts of the amino acid esters of THC. According to a sixth embodiment of the invention, there is provided a method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being 3a essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with the second embodiment as shown in scheme I H COOH 0 COOH R N 0 H N R H 2 0, NaHCO 3 , O N R DCC, DMAP,DCM 2 Allyl chloroformate H 'CO ,D 0 R = amino acid residue 2 (Neutral, acidic or basic) OH I 3 O DCM, phenyl silant THC Tetrakis(triphenylphosphine) palladium Methanol R R NH-C NH 2 R NH 2 O'CO O O'C' -' 0 10 1) DCC, DMAP,DCM, 2 2) DCM, phenyl silane O Tetrakis(triphenylphosphine) palladium 0 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) comprising the steps of: 1) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid, 4) reacting the allyl formate derivative of the second amino acid with THC-amino acid, 5) deprotecting the allyl formate derivative to generate the di-amino acid derivative of THC and 6) preparation of the water soluble salts of the amino acid esters of THC. According to a seventh embodiment of the invention, there is provided a method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with the third embodiment as shown in scheme I 3b H COOH 0 COOH R N 0 HN
H
2 ,NaHCO 3 N R DCC, DMAP,DCM
H
2 N Allyl chloroformate 0 HN OC.O 0 R = amino acid residue A 2 (Neutral, acidic or basic) OH I 3 O DCM, phenyl silan THC Tetrakis(triphenylphosphine) palladium Methanol R R NH- -INH 2 R NH 2 01 ' 0 OI ' 1)DCC, DMAP,DCM, 2 2) DCM, phenyl silane O Tetrakis(triphenylphosphine) palladium 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) comprising the steps of: 1 ) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid, 4) reacting the allyl formate derivative of the amino acid with THC amino acid, 5) deprotecting the THC amino acid coupled with allyl formate derivative of the amino acid, 6) reacting the allyl formate derivative of the amino acid with THC di-amino acid, 7) deprotecting the allyl formate derivative to generate the triamino acid derivative of THC and 8) preparation of the water soluble salts of the amino acid esters of THC. According to an eighth embodiment of the invention, there is provided a method of preparing the hemisuccinates and hemigluturates of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, of the first, second or third embodiments by reacting the compounds with succinic or glutaric anhydride in the presence of a base catalyst followed by the purification of the reaction mixture. According to a ninth embodiment of the invention there is provided a A 9 tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the first, second or third embodiments for use as a medicament. Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps. 3c The amino acid conjugation can yield THC prodrugs that are significantly more hydrophilic and that exhibit greater thermal, chemical and enzymatic stability. These compositions will provide significant treatment options for many disease states known to be ameliorated by THC, including emesis due to chemotherapy, wasting syndrome of HIV patients, multiple sclerosis, glaucoma, spasticity and pain. Administered in the proper formulation, these compositions will decrease the adverse effects of THC therapy (i.e. diminish the levels of the 11-OH-THC metabolite). Description of the invention THC-amino acid esters as prodrugs for THC were prepared in this invention by coupling of THC with allyl protected different amino acids to generate the THC-allyl protected amino acid esters which on deprotection produced THC-amino acid esters. THC (Fig. 1) is used as the starting material for all THC-amino acid esters. Brief Description of the Drawings Figure 1: Schematic representation of the utility of the prodrug /TMP system concept. Prodrug (PD) derivatization of the parent drug THC (D), in combination with the TMP system improves overall permeability. Transbuccal permeability and bioreversion are illustrated by arrows. Line thickness represents the extent and higher or lower rates of permeability. Figure 2: LC/MS of compound 6 (+ive mode) M+H = 414 Figure 3: Representative peaks in carbon spectroscopy for compound 6 Figure 4: GC/MS analysis of the hydrolysis product of 6 confirming a A 9 -THC derivative. 3d WO 2010/051541 PCT/US2009/062998 Figure 5: LC/MS of compound 7 (+ive mode) M+H = 386 Figure 6: LC/MS of compound 8 (+ive mode) M+H = 428 Figure 7 HREIMS of compound 9 (+ive mode) M+H = 443.29 and M+Na 465.27 Figure 8: Representative peaks in carbon spectroscopy for compound 9 Figure 9: HREIMS of compound 10 (+ive mode) M+H = 501.6, M+Na = 523.6 and M+K = 539.3 Figure 10: Representative peaks in carbon spectroscopy for compound 10 Figure 11: LC/MS of compound 11 (+ive mode) M+H = 478.3 Figure 12: HREIMS of compound 12 (+ve mode) M+H = Figure 13: LCMS of compound 13 (+ive mode) M+H = 476 Figure 14: Representative peaks in carbon spectroscopy for compound 13 Figure 15: LCMS of compound 14 (+ive mode) M+NH 4 = 593.7 Figure 16: Representative peaks in carbon spectroscopy for compound 14 Figure 17: LCMS of compound 15 (+ive mode) M+NH 4 += 531.7 Figure 18 Representative peaks in carbon spectroscopy for compound 15 THC prodrugs: Chemical modification of a therapeutic agent by way of prodrug design has become an important drug delivery tool["-"). This is one of the most widely accepted and successful strategies for modifying physicochemical characteristics, aqueous solubility, chemical and enzymatic stability and mucosal permeability of drug candidates through linkage of appropriate promoieties. A significant positive aspect of the prodrug approach is that it does not induce any change in the membrane structure, fluidity or characteristics. The prodrugs are cleaved in vivo to generate the active drug and the harmless pro-moiety, which is eliminated from the body (Fig. 1). Amino acid prodrugs: In the past decade amino acids have taken center stage as promoieties for transporter targeted prodrug derivatization of hydrophilic drug molecules 2 s- 31 ). Some studies exploiting this mechanism for circumvention of efflux proteins have also been publishedE 323 1 . A few studies exploring the use of single amino acid based prodrug derivatization to enhance hydrophilicity of lipophilic molecules and improve oral absorption have also been reported 1 28 36461. However, to date, transbuccal delivery of mono-, di- or tri- amino acid conjugated prodrugs of lipophilic compounds has 4 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 not been investigated. Indeed, a major gap in the understanding of the structural and physicochemical characteristics of any molecule necessary for transbuccal penetration exists. This route of administration holds tremendous untapped potential for the delivery of many therapeutic agents with limited permeability and metabolic stability. Compounds whose systemic bioavailability is limited by hepatic metabolism, as in the case of THC, will necessitate preparation of more permeable prodrugs, such as the mono-, di- and tri- amino acid esters to be formulated in non-oral formulations such as the Transmucosal Matrix Patch (TMP) system with a multitude of advantages. However, the above-cited prodrugs could also be incorporated into an oral delivery system and other compositions using processing techniques, including, but not limited to, hot-melt extrusion to enhance bioavailability. The highlight of this invention is the ability, for the first time, to prepare amino acid esters of THC, without affecting the basic structure of THC. Increasing the bioavailability of THC, through the use of the amino acid esters prodrugs and incorporating these prodrugs in a formulation such as the Transmucosal Matrix Patch (TMP), or a more efficient oral delivery system, could have a significant influence on many chronically ill patients, such as those infected with the HIV virus, those undergoing chemotherapy, as well as other conditions known to be ameliorated by THC, such as pain, spasticity and multiple sclerosis. The pharmacologically acceptable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical compositions useful in treatment of chronic states treatable with THC and which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers. The pharmaceutical compositions according to the invention are those which are suitable for enteral, such as oral, administration and for parenteral, such as subcutaneous, administration to warm-blooded animals, especially humans, and which contain the pharmacologically active substance on its own or together with a pharmaceutically acceptable carrier. A preferred method of use for the present compositions is by transmucosal patch. The dosage of the active substance depends on the species of warm-blooded animal and on the age and individual condition the illness to be treated and also on the mode of administration. THC-Amino Acid Prodrugs: SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 Computational analysis of the amino acid based THC prodrugs: Based on the previous findings, computational analysis, using Molecular modeling Pro@ software, was utilized to predict the physicochemical properties of various promoiety candidates. Computational analysis was subsequently performed with some of the amino acids classified under the hydrophobic amino acid group (e.g. alanine, leucine, valine), as well as with the hydrophilic amino acids (e.g. glycine, serine, sarcosine, aspartic acid, tyrosine and glutamine), and their combinations. These results are depicted in Table 1. Table 1: Computed physicochemical properties of select amino acid ester prodrugs of THC. Molecular modeling Pro Software was used for this purpose. Sr. No. Compound Molecular Molecular mLogP % hydrophilic Polar surface weight formula surface area area 1 THC 314.46 C 21
H
30 0 2 3.963 5.742 29.46 2 THC-Ala 385.54 C 24
H
35
NO
3 2.438 13.163 64.71 3 THC-Leu 427.61 C 27
H
4 1
NO
3 3.051 11.465 64.71 4 THC-Val 413.59 C 26 Ha 3
NO
3 2.850 11.889 64.71 5 THC-Gly 371.25 C 23
H
33
NO
3 2.227 16.702 64.71 6 THC-Ser 401.54 C 24
H
35
NO
4 3.183 22.742 84.94 7 THC-Sar 385.26 C 24
H
35
NO
3 2.438 21.070 50.72 8 THC-Asp 429.55 C 25
H
35
NO
5 3.286 21.844 105.17 9 THC-Tyr 477.63 C 3 oH 3 9 N0 4 2.683 16.064 84.94 10 THC-Tyr-Gln 605.8 C 35
H
47
N
3 0 6 4.27 28.687 163.45 11 THC.Tyr-(Gln) 2 733.9 C 40
H
5 5N 5
O
8 3.32 35.529 244.95 12 THC-Gln 442.28 C 26
H
38
N
2 0 4 2.36 22.833 110.96 13 THC-Gin-Val 541.35 C 31
H
47
N
3 0 5 4.95 25.434 143.22 14 THC-Gln-Val-Val 640.42 C 36
H
56
N
4 0 6 5.98 27.886 175.48 15 THC-Val-Gly 470.64 C 2 sH 42
N
2 0 4 4.296 20.319 96.97 16 THC-Val-Gly-Gly 527.70 C 30
H
45
N
3 0 5 5.782 27.276 129.23 The results predict a significant decrease in the logP values and increase in hydrophilicity with both hydrophilic and hydrophobic amino acid prodrugs evaluated. The polar surface area and the % hydrophilic surface area are also significantly improved. Additionally the di- and tri- amino acid (peptide) linkages will allow significant modulation of the physicochemical properties. Thus depending on the type of amino acid selected and the number of amino acids linked to THC, a wide range of 6 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 hydrophilicities can be generated and permeabilities determined. Thus the correlation of logP and permeability can be determined. THC-Amino acid esters synthesis: Several procedures were attempted for the preparation of the A 9 -THC amino acid derivatives using the t-boc and F-moc protected amino acids. While the formation of the esters with the protected amino groups was not problematic for all of the amino acid derivatives attempted, deprotection of the t-boc or the F-moc groups under various deprotection conditions always resulted in conversion of the
A
9 -THC (at least in part) to A 8 -THC, in case of the t-boc, or reversion to A 9 -THC in the case of the F moc. In this invention, we have developed allyl protected amino acids prepared in house (scheme 1) to overcome the problems associated with the commonly available protected amino acids. This approach proved to be successful and promises viability in the preparation of any amino acid derivative or small chain peptide derivatives of A 9 -THC without any effect on the rest of the structure. The di-amino acid derivative could be converted to the tri-amino acid derivative following the same procedure as for the conversion of the mono- to the di- derivative. H COOH 0 COOH R N 0 A ~~H 2 0, NaHo 3 ~ Arr
H
2 N R Allyl chloroformate 0 N R DCC, DMAP,DCM cr Co R = amino acid residue Ayzrm 2 H 0CO (Neutral, acidic or basic) - OH 1 N0 0 3 THC DCM, phenyl silan Tetrakis(triphenylphosphine)palladium Methanol R R NH, kNH 2 R NH 2 Y Y 1 o ' 01 '0 1)Dcc, DMAP,DCM, 2 2) DCM, phenyl silane O Tetrakis(triphenylphosphine) palladium 0 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) General scheme for the preparation of mono, di and tri-amino acid THC derivatives. Scheme I. Examples of amino acid esters prepared according to scheme 1, are: 6 9 -THC-valinate (6), THC sarcosinate (7), THC-leucinate (8), THC-glutaminate (9) THC-tryptophinate (10), THC-tyrosinate (11) 7 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 and THC-B-alaninate (12) were prepared. The compounds THC-4-(4-amino-phenyl) butyrate) (13), and THC-4-(4-amino-phenyl) butyrate)hemisuccinate (14) and THC-valinate-hemisuccinate (15) were prepared using scheme II. Their structures were confirmed by mass (LC/MS and HREIMS) and spectroscopic analysis ('H-NMR and 3 C-NMR). 8 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998
H
2 N H H 2 N 0 0x 00 Chemical Formula: C 2 6
H
3 9
NO
3 Chemical Formula: C 24
H
35
NO
3 Chemical Formula: C 2 6
H
3 9 NO3 Molecular Weight: 413.5928 Molecular Weight: 385.5396 Molecular Weight: 413.5928 THC-valinate (6) THC-sarcosinate (7) THC-leucinate (8) OH 0 0 0 H 2 N OK - ' 'NH 2 N 0 - N O N NH 2 N NH 2 NH Chemical Formula: C 26
H
3 8N 2 0 4 Chemical Formula: C 3 2
H
40
N
2 0 3 Chemical Formula: C 3 0
H
3 9 NO4 Molecular Weight: 442.5909 Molecular Weight: 500.6716 Molecular Weight: 477.6350 THC-glutaminate (9) THC-tryptophanate (10) THC-tyrosinate (11) x NH 2 N11-12
NH
2 N 0 0N 0 N O 00 Chemical Formula: C 2 4
H
3 5
NO
3 Chemical Formula: C 3 1
H
41 NO3 Molecular Weight: 385.5396 Molecular Weight: 475.6621 THC-B-alaninate (12) THC-4-(4-amino-phenyl)butyrate (13) 9 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 H O O OHO 'N 0 0N 0.l 0 OOH Of 00 0 ~ 0' 0 Chemical Formula: C 3 aH 4 5
NO
6 Chemical Formula: C 30
H
4 3
NO
6 Molecular Weight: 575.7349 Molecular Weight: 513.6655 THC-4-(4-amino-phenyl)butyrate hemisuccinate (14) THC-valinate-hemisuccinate (15) Examples (compounds 6-15) Example 1: Preparation of A 9 -THC-valinate (6): Following the general procedure outlined in Scheme i, where compound i is valine, A 9
-THC
valinate 6 was synthesized to test the validity of the synthetic protocol. Valine (5 g) was dissolved in 34 mL of distilled water and 5.8 gram of sodium carbonate was added in several portions. Allyl chloroformate (10 mL) was added at once after the bubbling stopped. The solution was stirred for 24 hours at 22 0 C. Concentrated hydrochloric acid was then used to adjust the pH to 1. The solution was extracted with ethyl acetate 8 times and the organic layer was rinsed with brine and dried over sodium sulfate. The solvent was evaporated to dryness to give 6.5 g of the crude product as a colorless syrup. A 1.1 equivalent of this product was dissolved in dichloromethane and 1.1 equivalent of DCC was added to it (solution A). A 9 -THC (1 equivalent) was dissolved in dichloromethane along with a catalytic amount of DMAP (dimethyl amino pyridine) which was added drop-wise to solution A. The reaction mixture was stirred at room temperature for 1 hour and the reaction progress was monitored through TLC. After one hour the reaction mixture was worked up and the product was purified using silica gel column chromatography. Fractions having the product were combined and evaporated to obtain the protected A 9 -THC-valine ester (95% yield), which was confirmed by mass spectroscopy. The latter was dissolved in dichloromethane and 0.05 mmol of tetrakis(triphenylphosphine) palladium was added along with 0.01 mmol of phenyl silane. The reaction was allowed to stir at room temperature for 30 minutes. The solvent was then evaporated and the product 6 was purified using column chromatography (>87% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 414.5) (Fig 2). The structure of product 6 was also confirmed by spectral analysis 1
H
NMR and 13 C-NMR (see Fig 3 for 1 3 C-NMR assignments). 10 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 For confirmation that the product 6 is the derivative of A 9 -THC and not converted to A 8 -THC, compound 6 was base hydrolyzed followed by GCIMS analysis of the hydrolysis product. The analysis confirmed that it is pure A 9 -THC as shown in Figure 4. Example 2: Preparation of A 9 -THC-sarcosinate (7): Following the general procedure outlined in Scheme 1, where compound 1 is sarcosine, A 9 THC- sarcosinate 7 was synthesized. Product 7 was purified using column chromatography (>80% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 386) (Fig. 5). The structure of product 7 was also confirmed by spectral analysis 1 H-NMR and "C-NMR. Example 3: Preparation of Ag-THC-leucinate (8): Following the general procedure outlined in Scheme 1, where compound 1 is leucinine, A 9 THC- leucinate 8 was synthesized. Product 8 was purified using column chromatography (>81% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 428) (Fig. 6). The structure of product 6 was also confirmed by spectral analysis 'H-NMR and 1 3 C-NMR. Example 4: Preparation of A 9 -THC-cilutaminate (9): Following the general procedure outlined in Scheme I, where compound 1 is glutamine, A 9 THC-glutaminate 9 was synthesized. Product 9 was purified using column chromatography (>85% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 443) (Fig 7). The structure of product 9 was also confirmed by spectral analysis ( 1 H-NMR and 1 3 C-NMR (see Fig 8 for 1 3 C-NMR assignments). Example 5: Preparation of A"-THC-tryptophinate (10) Following the general procedure outlined in Scheme 1, where compound 1 is tryptophan, A 9 THC- tryptophinate 10 was synthesized. Product 10 was purified using column chromatography (>86% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 501) (Fig 9). The structure of product 10 was also confirmed by spectral analysis 'H-NMR and 13 C-NMR (see Fig 10 for 13 C-NMR assignments). 11 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 Example 6: Preparation of A'-THC-tyrosinate (11) Following the general procedure outlined in Scheme 1, where compound I is tyrosine, A 9
-THC
tyrosinate 11 was synthesized. Product 11 was purified using column chromatography (>82% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 478.3) (Fig 11). The structure of product 10 was also confirmed by spectral analysis 'H-NMR and "C-NMR. Example 7: Preparation of Ag-THC-0-alaninate (12) Following the general procedure outlined in Scheme 1, where compound 1 is B-alanine, A 9 THC- P-alaninate 12 was synthesized. Product 12 was purified using column chromatography (>82% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 386.3) (Fig 12). The structure of product 6 was also confirmed by spectral analysis 'H-NMR and "C-NMR. Example 8: Preparation of A 9 -THC-4-(4-aminophenyl)butyrate (12): Following the general procedure outlined in Scheme 1, compound 12 was synthesized, where compound I was 4-(4-aminophenyl)butyrate and was used without any protection. Product 12 was purified using column chromatography (>90% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+H = 476) (Fig 13). The structure of product 12 was also confirmed by spectral analysis 'H-NMR and "C-NMR (see Fig 14 for 1 3 C-NMR assignments). Scheme 11: 12 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998
INH
2 H NOH OH O 00 DCM,DMAP O 0 + 0 0 0 Et 3 N 0
C
4
H
4 0 3 0 Chemical Formula: C31 H 41
NO
3 Exact Mass: 100.0160 0 Molecular Weight: 475.6621 succinic anhydride Chemical Formula: C 35
H
45
NO
6 THC-4(4-aminophenyl)butyrate Molecular Weight: 575.7349 (13) (14) Scheme for the preparation of THC hemisuccinate derivatives. Scheme || Example 9: Preparation of THC-4(4-aminophenyl)butyrate-hemisuccinate (14): THC-4(4-aminophenyl)butyrate (13) was dissolved in 50 mL of dichloromethane and 1.1 eq of succinic anhydride was added along with catalytic amount of DMAP (di-methyl amino pyridine). 1.1 eq. of triethyl amine was added drop wise with a syringe and reaction was allowed to run overnight at room temperature. In the morning, TLC indicated complete conversion of the starting material to product. Solvent was evaporated up to approximately one third of volume on rotavap, and then 1 mL of DCM was added in it. A column was packed with silica gel (10 eq.) in DCM and the reaction mixture, which was dissolved in DCM, was loaded at the top'of the column. Fractions were collected initially in DCM and then increased to 50% EtOAc. Product came in 40 % EtOAc in DCM. Fractions containing pure product were combined and the solvent was evaporated to dryness to get the product (14) (95% yield). Product 14 was confirmed by mass spectroscopy in the positive ionization mode (M+NH 4 = 593) (Fig 15). The structure of product 14 was also confirmed by spectral analysis 'H-NMR and 13C NMR (see Fig 16 for 13 C-NMR assignments). Example 10: Preparation of THC-valinate.hemisuccinate (15): Compound 15 was also prepared using scheme 11, where the starting material was compound 6 (THC-valinate). Product 15 was purified using column chromatography (>85% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+NH 4 ' = 531) (Fig 17). The structure of 13 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 product 15 was also confirmed by spectral analysis 1 H-NMR and "C-NMR (see Fig 18 for "C-NMR assignments). Spectral analysis of A 9 -THC prodrugs prepared above: Identity and purity of the synthesized prodrugs was established by spectral means including 'H-NMR, "C-NMR and 2D-NMR such as COSY, HMQC, HMBC, as well as other spectroscopic means (IR, UV and MS). The synthetic protocols outlined above yielded prodrugs with 295% purity. 14 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 Example 11: THC Prodrugs Preformulation Data A. Solubility a. Aqueous Solubility (pM) THC- THC- THC- THC- TH)C- THC- THC. THC-APB pH THC Sarcosine THC-Vailne Va ine Vaine-HS Leucine Glutamine Tyrsine Tryptophan Tr1tophaa HS I ~ ~malonate M~nt 1.2 - 263.16±75.84 78.23±0.66 103.61±2.11 0.12±0.06 21.8910.26 134.2510,05 87.76±4.48 - 0.95±0.12 0 2 0.95 393.89±24.21 147.35±24.90 228.78±9.79 0.1710.06 55.46±0.93 367.06±32.44 33.00±1.38 0 2.81±0.19 0 3 2.23 250.54±7.38 69.78±0.33 96.65±3.49 0.00 12.08±1.40 104.3612.55 11.06t3.73 - 0 0 4 1.27 131.70±5.13 24.10±1.28 26.88*3.01 0.00 4.33±0.20 50.1314.97 1.52±0.06 - 0 0 5 2.23 18.54±1.87 3.51t0.62 2.36+0.01 0.67±0.04 0.54±0.06 12.99±0.04 0 0 0 0 6 2.23 1.3810.18 0.17±0.00 0.2510.04 24.80±3.51 0.19±0.02 4.84i0.72 0 - 0 0 7 2.23 0.00±0.00 0.00±0.00 0.110.03 303.06±60.72 0.00±0.00 1. 8 14 0 0 0 64.66±0.97 8 2.23 0.0010.00 0.00±0.00 0.120.0I 227.86±21.24 0.00i0.00 0.7610.74 0 - 0 110.20±26.12 9 - 0.000.00 0.00±0.00 0.2710.03 0.05±0.00 0.00i0.00 0.35±0.04 0 0 0 41.45±7.59 Water 2.23 0.00±0.00 0000.00 2.33i1.19 16.54±11.69 0.00±0.00 3.631.0 0 8.028.90 0 15 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 b. Aqueous Solubility (pg/ml) THC- THC- THC- THC. THC- THC- THC- THC- THC-APB pH THC Sarcosinate Valinate(6) Valinate Valinate-HS Leucinate Glutaminate Tyrosinate Tryptophanate Tryptophadate HS (14) (7) malonate (15) (8) (9) (11) (10) Malenate 101.38±29.22 32.16±0.27 53.63±1.09 0.06±0.03 9.36±0.11 59.55±0.02 41.92±2,14 1.58±0.19 0.00 2 0.95 151,75±9.33 53.66±10.30 118.42l5.07 0.09±0.03 23.71±0.40 162.82±14.39 15.76±0.66 0.00 4.65f0.31 0.00 3 2.23 96.52±2.84 28.76±0.14 50.03.1.80 0.00 5.17;0.60 46.29±1.13 5.28±1.78 - 0.00 0.00 4 1.27 50.74±1.98 10.34±0.53 13.92±1.56 0.00 1.95±0.09 22.2412.20 0.73±0.03 - 0.00 0.00 5 2.23 7.14±0.72 1.27±0.25 1.22±0.00 0.35±0.02 0.23±0.03 5.76±0.02 0.00 0.00 0.00 0.00 6 2.23 0.53±0.07 0.07t0.00 0.13±0.02 12.74±1.80 0.08t0.01 2.1510.32 0.00 - 0.00 0.00 7 2.23 0.00 0.00 0.05±0.02 155.67±31.19 0.00 0.52±0.06 0.00 0.00 0.00 37.22±0.56 8 2.23 0.00 0.00 0.06±0.00 117.04±10.91 0.00 0.34±0.33 0.00 - 0.00 63.45:15.04 9 - 0.00 0.00 0.14±0.02. 0.02±0.00 0.00 0.16±0.02 0.00 0.00 0.00 23.86±
H
2 0 2.23 0.0 0.05 1.21±0.61 8.50±6.00 0.0 1.61±0.76 0.00 0.00 13.27±14.72 0.00 B. Chemical Stability pH Dependent at 25 0 C First order rate constant (x10~ 3 h-) Medium TC THC- THC- THC- THC- THC- THC- THC- THC-APB THC Sarcosinate (7) Valinate (6) Vanate-HS Leucinate (8) Glutaminate Tyrosinate Tryptophanate HS (14) (15) (9) (11) (10) . Buffer pH 5.0 17.00 38.35±4.32 4.06±0.01 Stable 15.94±3.38 70.23±0.92 6.32t3.14 8.29 3.68 Buffer pH 7.0 9.80 605.61±i25.14 47.13±1.16 Stable 85.91±16,83 153.42±4.26 25.02±0.88 38.03 Stable Buffer pH 9.0 - 1209.25t203.0 67.64±7.67 Stable 119.98±33.51 756.35±106.61 53.88±11.36 - Stable 5 Water - 25.45t21.99 23.70±0.77 Stable 8.51+2.80 32.72+15.19 9.4040.88 - 4.8110.81 16 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 C. Thermal Stability - 120 0 C for 10 min. Drug Initial, pg (%) Drug remaining, pg (%) Drug loading THC 1280.70±108.77 (100) 1214.0539.12 85.38i7.25 THC (95.05;L5.05) 8.872 CBN 56.76±4.86 53.85±1.60 THC- THC 26.68±3.80 54.53±3.35 THC- 79.82±0.85 Sarcosinate (7) CBN 40.05±3.45 33.83±0.97 THC-Sarcosinate (7) 1197.24t12.69 (100) 841.38±40.18 (70.3014.10) THC 61.91±9.49 74.3515.26 CBN 8.2711.68 8.79±2.43 104.6712.22 THC-Valinate 1440.57t46.34 (6) THC-Valinate (6) 1570.09±33.27 (100) (91.80±4.90) THC -6.13±0.84 25.86i0.83 THC- CBN 16.34±0.50 20.27±0.43 103.65±4.12 Leucinate (8) THC-Leucinate (8) 1554.80±61.76 (100) 1383.29140.73 ______________ (88.99±0.92) ________ THC 92.95±3.08 123.75±2.69 THC- 'CBN 35,68±1.16 24.42±0.21 inate (11) THC-T yrosinate (11) 1222.61i64.25 (100) 1138.93±60.67 81.51±4.28 (93.15±0.06) THC 97.3816.39 96.10±16.64 THC- CBN 25.59±2.26 16.63±2.63 Tryptophanate THC-Tryptophanate 1347.57±67.93 (100) 1216.70+32.88 89.84±4.53 (10) (10) (90.47±7.00) THC 96.52±3.72 80.26±8.59 THC-Valinate- CBN 0 0 Hs (15) THC-Valinate-HS 1411.49t45910 (100) 1350.13:387.10 112.2114.99 (15) (96.29±3.89) THC 0 0 CBN 47.63±9.92 38.36±9.70 THC-APB-HS THC-APB-HS (14) 1449.90±32.76(100) 1518.84±34.38 96.66±2.18 (14) (104.81±4.74) THC 0 0 CBN 0 0 THC- TCGuaiae6.125 GIutaminate TH(C-Glutannate 951.08±38.55 (100) 721.31±73.76 (75.75±4.69) 63.41+.57 (9) THC 161.87±3.06 189.89±7.16 CBN 32.34*0.69 89.43119,28 17 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 D. Bioreversion a. Plasma Stability Drug Parameters Porcine Plasma Rabbit Plasma THC-Valinate (6) K (x10~ 2 min~') 91.16i10.91 61.94±6.01 Tj 1 2 (min) 0.766±0.092 1.124±0.109 THC-Sarcosinate K (xlO 2 min~') 63.16±10.44 (7) Tin(min) 1.11±0.18 THC-Leucinate (8) K (x10 2 min-') 42.70±3.58 33.84±10.92 Tin(min) 1.629±0.137 2.160±0.697 THC-Glutaminate K (x10-2min~) 53.41±5.84 (9)
T
1 , (min) 1.31+0.14 THC- K (x10- 2 min~') 48.55±5.90 Tryptophanate (10) Ti/ (min) 1.44+0.17 THC-Tyrosinate K (x10~ 2 min~) 93.53±8.79 (11) T1, 2 (min) 0.74±0.07 THC-APB-HS (14) K (x1O- 2 min-) Stable T 1 2 (min) Stable THC-Valinate-HS K (X10-2min~ ) 85.54±3.74 (15)
T
1
/
2 (min) 8.1110.35 18 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 b. Porcine Buccal Tissue Homogenate Stability Protein Concen ration 2mg/ml Drug Parameters Porcine Tissue Control (IPBS) THC-Valinate (6) K (x10- 3 min~) 16±0.19 3.66±0.68 Tin (min) 43.30±0.51 192.50±35.62 THC-Sarcosinate K (xlO 3 min-') 37.36±3.87 23.47±1.60 (7) Tin (min) 18.91±0.4 3 29.59±2.01 THC-Leueinate (8) K (xlO~mini) 22.98±1.49 5.49±0.46
T
1 n(min) 30.21±1.95 126.70±10.63 THC-Glutaminate K (x 10min-1) 40.41±3.30 26.30±0.14 (9) Tin 2 (min) 17.21±1.40 26.35±0.14 THC- K (x0- 3 min-) 9.06±1.26 0.77±0.02 Tryptophanate (10) T 1 1 2 (min) 77.27±10.73 903.12±29.55 THC-Tyrosinate K (xlO 3 min~') 21.52±0.55 1.11±0.04 (11)
T
1 2 (min) 32.21+0.81 627.59±25.89 THC-Valinate-HS K (x1O 3 min') 2.96+0.19 0.40±0.02 (15) Tin (min) 23.43±1.49 1663.15±98.62 19 SUBSTITUTE SHEET (RULE 26) WO 2010/051541 PCT/US2009/062998 References: 1. Marijuana and Medicine: Assessing the Science Base, ed. JEF.Joy. SJ. Watson, and, J.A. Benson. 1999, Washington, DC: National Academy Press. 2. Martin, B.R., The use of cannabinoids in patients wilt chronic illness. 1.S. Pharmacist, 2002. 1: p. 61 3. ElSolhy, NIA, . Harland, and C.W. Waller, Cannabinoids in Glaucoma 1: The ec of different cannabinods on the intraocular pressure of the rabbit. Curr Eye Res, 1984, 3(6): p. 841-850, 4. E 1 -Mallakh, R.S., Mlarihuana and migraine. Headache, 1987. 2(8): p. 442-443. Z. Volfe, Z., IA, Dvilansky, and 1. Nathan, Cannabinoids block release of serotoninjfom platelets induced by plasma from migraine patients. Int. J Clin. Pharmacol. Res., 1985. 5(4): p. 243-246. 6. 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Claims (15)
1. A A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, of the formula 0 OUR o- R 1 0 wherein R1 is valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof.
2. A A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the formula wherein R1 and R2 are each valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof.
3. A A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of the formula wherein R1, R2 and R3 are each valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine or a salt thereof. 23
4. The hemisuccinate or hemigluturate derivatives of compositions of any one of claims 1 to 3.
5. Method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with claim 1 as shown in scheme I H COOH 0 COOH R N 0 HH 2 , NaHCO 3 O N R DCC, DMAP,DCM H 2 R Allyl chloroformate 0 C*O 0 R = amino acid residue A. 2 (Neutral, acidic or basic) OH 1 0 3 3 0 DCM, phenyl silan THC Tetrakis(triphenylphosphine) palladium Methanol R R NH - 0 > NH 2 R NH 2 1) DCC, DMAP,DCM, 2 2) DCM, phenyl silane Tetrakis(triphenylphosphine) palladium 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) comprising the steps of: 1) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid and 4) preparation of the water soluble salts of the amino acid esters of THC.
6. Method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with claim 2 as shown in scheme 1 24 H COOH 0 COOH R N 0 HAN H 2 0, NaHCO 3 O N R DCC, DMAP,DCM i r H 2 RAllyl chloroformate H O C 0 R = amino acid residue A- 2 (Neutral, acidic or basic) OH 1 0 3 DCM, phenyl silan THC Tetrakis(triphenylphosphine) palladium Methanol RI R NH - NH2 R NH 2 N I -' 0 N I ' 1) DCC, DMAP,DCM, 2 2) DCM, phenyl silane 0 Tetrakis(triphenylphosphine) palladium 0 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) comprising the steps of: 1) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid, 4) reacting the allyl formate derivative of the second amino acid with THC-amino acid, 5) deprotecting the allyl formate derivative to generate the di-amino acid derivative of THC and 6) preparation of the water soluble salts of the amino acid esters of THC.
7. Method of preparation of a A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 - tetrahydrocannabinol amino acid esters, in accordance with claim 3 as shown in scheme I H COOH 0 COOH R N O HNH 2 0, NaHCO 3 O N R DCC, DMAP,DCM Y 2 R Allyl chloroformate H O C O R = amino acid residue - 2 (Neutral, acidic or basic) "- OH 1 T DCM, phenyl silanE THC Tetrakis(triphenylphosphine) palladium Methanol R NH - NH R NH 2 ON C O OC O 1) DCC, DMAP,DCM, 2 2) DCM, phenyl silane O Tetrakis(triphenylphosphine) palladium 0 5 Methanol 4 (Di-amino acid derivative) (Mono amino acid derivative) 25 comprising the steps of: 1) preparing the allyl formate derivative of the amino acid, 2) reacting the allyl formate derivative of the amino acid with THC, 3) deprotecting the THC allyl formate derivative of the amino acid, 4) reacting the allyl formate derivative of the amino acid with THC amino acid, 5) deprotecting the THC amino acid coupled with allyl formate derivative of the amino acid, 6) reacting the allyl formate derivative of the amino acid with THC di-amino acid, 7) deprotecting the allyl formate derivative to generate the triamino acid derivative of THC and 8) preparation of the water soluble salts of the amino acid esters of THC.
8. A method of preparing the hemisuccinates and hemigluturates of a A 9 tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of any one of claims 1 to 3 by reacting the compounds with succinic or glutaric anhydride in the presence of a base catalyst followed by the purification of the reaction mixture.
9. Method in accordance with claim 8, wherein the base catalyst is a mixture of dimethylaminopyridine and triethylamine.
10. A A 9 -tetrahydrocannabinol amino acid ester composition, being essentially free of A 8 tetrahydrocannabinol amino acid esters, of any one of claims 1 to 4 for use as a medicament.
11. A A 9 -tetrahydrocannabinol amino acid ester composition when obtained by a method of any one of claims 5 to 9.
12. A composition of any one of claims 1 to 3, substantially as herein described with reference to any one of Examples 1 to 7.
13. A method of preparation of compositions of claim 12, which method is substantially as herein described with reference to any one of Examples 1 to 7.
14. The hemisuccinate or hemigluturate derivatives of compositions of any one of claims 1 to 3, substantially as herein described with reference to Example 10. 26
15. A method of preparing the composition of claim 14, which method is substantially as herein described with reference to Example 10. 27
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2009
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- 2009-11-02 WO PCT/US2009/062998 patent/WO2010051541A2/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
JP5739344B2 (en) | 2015-06-24 |
EP2352497A4 (en) | 2012-08-01 |
US8809261B2 (en) | 2014-08-19 |
HK1158517A1 (en) | 2012-07-20 |
US9630941B2 (en) | 2017-04-25 |
EP2352497A2 (en) | 2011-08-10 |
AU2009308665A1 (en) | 2010-05-06 |
DK2352497T3 (en) | 2017-04-03 |
CA2741862C (en) | 2017-10-17 |
US20110275555A1 (en) | 2011-11-10 |
CA2741862A1 (en) | 2010-05-06 |
WO2010051541A3 (en) | 2010-07-08 |
JP2012507568A (en) | 2012-03-29 |
US20150045282A1 (en) | 2015-02-12 |
ES2622582T3 (en) | 2017-07-06 |
PL2352497T3 (en) | 2017-08-31 |
WO2010051541A2 (en) | 2010-05-06 |
EP2352497B1 (en) | 2017-02-22 |
HUE032158T2 (en) | 2017-09-28 |
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